State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China.
Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, Bethesda, Maryland.
J Nucl Med. 2018 Sep;59(9):1386-1391. doi: 10.2967/jnumed.117.205088. Epub 2018 Apr 13.
One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog (I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of I-IBA-CP toward HER2 in vitro and in vivo. Additionally, I-ICP was prepared by direct radioiodination of CP724,714 for comparison with I-IBA-CP. IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of I-IBA-CP than of I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. The radiolabeled HER2-selective inhibitor I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
乳腺癌中最具临床相关性的分子异常之一是人类表皮生长因子受体 2（HER2）的过度表达。我们旨在开发用于 HER2 靶向乳腺癌成像的放射性标记酪氨酸激酶抑制剂。在这项研究中，我们制备了 HER2 选择性抑制剂 CP724,714 的放射性碘类似物（I-IBA-CP），并在 HER2 阳性或阴性的皮下人乳腺癌异种移植模型中进行了评估。CP724,714 类似物 IBA-CP 被合成并检测其对 HER2 和其他 6 种酪氨酸激酶的抑制活性。I-IBA-CP 是使用铜介导的放射性碘标记方法制备的，具有增强的标记产率和摩尔活性。在不同细胞系中评估了体外生物学活性，包括 I-IBA-CP 与其 HER2 激酶靶标的特异性和非特异性结合。在携带 HER2 阳性、HER2 阴性或表皮生长因子受体（EGFR）阳性肿瘤的小鼠中进行了小动物 SPECT 成像和生物分布研究。使用非放射性 IBA-CP 和 EGFR 抑制剂厄洛替尼作为阻断剂，在体外和体内研究 I-IBA-CP 与 HER2 的结合特异性和选择性。此外，通过直接碘化 CP724,714 制备 I-ICP 进行比较。IBA-CP 显示出优越的体外抑制活性（半最大抑制浓度，16 nM）和对 HER2 的选择性，优于其他 6 种与癌症相关的酪氨酸激酶。I-IBA-CP 的典型放射化学产率约为 65%（衰变校正），放射化学纯度超过 98%，合成结束时的摩尔活性为 42GBq/μmol。SPECT 成像显示，I-IBA-CP 在 HER2 阳性 MDA-MB-453 肿瘤中的摄取明显高于 I-ICP。在 HER2 阴性 MCF-7 肿瘤中的摄取要低得多。IBA-CP 的过量注射可阻断 MDA-MB-453 肿瘤中 I-IBA-CP 的结合，但不能阻断厄洛替尼。放射性标记的 HER2 选择性抑制剂 I-IBA-CP 是一种有前途的探针，可用于体内检测 HER2 阳性肿瘤。
